Authors
Nordeval Cavalcante Araújo1 José Hermógenes Rocco Suassuna1
1Universidade do Estado do Rio
de Janeiro, Departamento de Nefrologia, Rio de Janeiro, RJ, Brasil.
Submitted on: 05/21/2020. Approved on: 08/31/2020.
Correspondence to: Nordeval Cavalcante Araújo. E-mail: nordevalaraujo@gmail.com
O tamanho do baço em pacientes em hemodiálise
Introdução: A inflamação promove a
progressão da insuficiência renal crônica, e o início da diálise agrava a inflamação. O aumento do baço está associado à inflamação e os pacientes em hemodiálise podem apresentar um baço grande. O objetivo do presente estudo foi comparar o tamanho do baço de pacientes em hemodiálise versus aquele de controles, para atualizar este tópico. Métodos: Controles e pacientes foram elegíveis para participar do estudo desde que fossem negativos para marcadores sorológicos dos vírus da hepatite B, C e HIV, se não apresentassem distúrbio linfoproliferativo e tivessem pelo menos 18 anos de idade. Registramos idade, sexo e duração da diálise. Avaliamos as variáveis laboratoriais (hemoglobina, contagem de células hematológicas, creatinina sérica) e a causa básica da doença renal terminal. O tamanho dos baços dos pacientes foram divididos em tercis. Resultados: Os 75 controles e 168 pacientes selecionados foram pareados por sexo. Os pacientes eram mais velhos, tinham baços maiores e menor contagem de plaquetas do que os controles. A relação entre o tamanho do baço e a idade dos controles e pacientes foi bastante semelhante. Os pacientes do primeiro tercil de tamanho do baço, em comparação com os do terceiro, eram mais velhos e apresentavam contagens de plaquetas mais altas. A doença subjacente e o período de diálise não tiveram efeito no tamanho do baço. Discussão: Os pacientes tinham baços maiores e uma maior variedade de tamanhos de baço do que os controles. Entre os pacientes, a associação entre baço maior e menor com contagens de plaquetas mais baixas e mais altas, respectivamente, gerou a especulação da ocorrência de hiperesplenismo e hiposplenismo.
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esumoIntroduction: Inflammation promotes the progression of chronic renal failure, and the start of dialysis worsens inflammation. The enlargement of the spleen is associated with inflammation, and patients on hemodialysis may show a large spleen. The aim of the present study was to compare the spleen size of patients undergoing hemodialysis versus controls to update this thread. Methods: Controls and patients were eligible to participate in the study provided they were negative for serological markers of hepatitis B and C viruses and HIV, if they had no lymphoproliferative disorder, and if they were at least 18 years of age. Age, sex, and the duration of dialysis were recorded. Laboratory variables (hemoglobin, hematological cell count, serum creatinine) and the underlying cause of end-stage renal disease were analyzed. The spleen sizes of the patients were divided into tertiles. Results: The 75 controls and 168 patients selected were sex-matched. The patients were older, had larger spleens and lower platelet counts than controls. The relationship between spleen size and age in the controls and patients was quite similar. The patients in the first tertile of spleen size compared with those in the third were older and had a higher platelet counts. The underlying disease and dialysis vintage had no effect on spleen size. Discussion: The patients had larger spleens and a greater range of spleen sizes than the controls. In patients, the association between larger and smaller spleen with lower and higher platelet counts, respectively, sparked the speculation of occurrence of hypersplenism and hyposplenism.
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bstRActDOI:
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ntRoductIonInflammation has a role in the progression of chronic renal failure1, regardless of the etiology. In
end-stage renal disease, the start of dialysis treatment acts as a triggering event that worsens inflammation2.
In addition, repeated dialysis treatments lead to leu-cocyte activation and, consequently, the production of cytokines3. The persistence of inflammation
con-tributes to the overall and cardiovascular mortality associated with this condition4.
The pathophysiology of inflammation includes recruitment of leucocytes to the spleen5, and
enlarge-ment of the organ has been reported to be associated with inflammation6. According to publications from
the 1970s and early 1980s, patients undergoing he-modialysis showed enlargement of the spleen7-9. In line
with this latter finding, it is well-known that hypers-plenism may appear in patients undergoing regular hemodialysis10. On the other hand, hyposplenism has
also been reported to be associated with some condi-tions that cause end-stage renal disease (ESRD)11-12.
Moreover, the association between hyposplenism and renal transplantation has been established based on Howell-Jolly bodies in blood smears13 and
hepatos-plenic scintigraphy14.However, it has not been
deter-mined if hyposplenism develops after transplantation or if the condition is already present before starting immunosuppression.
The aim of the present study was to shed light on this issue by comparing the spleen size in patients un-dergoing hemodialysis versus a control group and by analyzing the determinant factors related to the leng-th of leng-the spleen to update leng-this leng-thread.
m
AteRIAls Andm
ethodsThis was a cross-sectional study carried out in the nephrology facility of the Hospital Pedro Ernesto of the University of the State of Rio de Janeiro. All kid-ney donor candidates and ESRD patients undergoing renal replacement therapy referred for sonography in the period from 2008 to 2019 were eligible to partici-pate in the study. Since 2010, most sonography exa-mination at our facility have involved evaluation of the kidneys and spleen. In accordance with the aim of the study, only cases in which kidney and spleen were scanned at the same time were enrolled in the study.
The inclusion criteria were as follows: (1) negative serological markers of hepatitis B (HBsAg) and he-patitis C (anti-HCV) viruses and human immunode-ficiency virus (anti-HIV), (2) no lymphoproliferative disorder, and (3) at least 18 years of age. Patients on peritoneal dialysis and those referred for hemo-dialysis under immunosuppressive treatment becau-se of early or late renal transplant dysfunction were excluded.
In addition to age and sex, the duration of dialy-sis treatment was also recorded. Laboratory varia-bles (hemoglobin, hematological cell count, and se-rum creatinine) and the underlying cause of ESRD were obtained from medical records of the patients.
A platelet count of <150,000/mm3 was used as the
threshold value for diagnosis of thrombocytopenia15,
while a platelet count higher than 450,000/mm3 was
indicated as thrombocytosis16.
The protocol for spleen sonography has already been reported elsewhere13. In brief, different angles
of insonation at different sites were performed in or-der to display the best image, in which the most cra-nial and most caudal edge of the spleen were seen in the scan plane for measuring spleen length. All ultra-sound studies were performed by the same observer (NCA).
s
tAtIstIcAlA
nAlysIsThe normality of data distribution was assessed by means of the Wilks-Shapiro test. In accordance with normality of data, the continuous variables studied in the controls and patients on hemodialysis were compared using parametric (Student’s t-test) or non--parametric tests (Mann-Whitney test). The streng-th of streng-the relationship between continuous variables was evaluated using Pearson’s correlation coefficient. The associations between categorical variables were evaluated using the Chi-square test. The spleen size values of the study group were divided into tertiles. The subsets (tertiles) were defined by spleen size cut--off values reflecting the 33rd and 66th percentiles of spleen size distribution. The statistical significance threshold was set at p<0.05.
The institutional ethics committee approved the study protocol with the waiver for informed consent due to the retrospective nature of the study.
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esultsFrom May 2010 until February 2020, out of 3009 sonograms performed in 1281 different subjects, sple-en sonograms were available for 1070 subjects. Of these, 763 patients were excluded because they were transplanted (440 patients), were on conservative tre-atment (297 patients), or were on continuous ambu-latorial peritoneal dialysis (26 patients).
Seventy-five subjects with normal renal function, including renal donor candidates, patients with minor renal abnormalities (microscopic hematuria, kidney sto-ne patients without obstruction, non-sto-nephrotic protei-nuria), and patients referred for routine health check-up, were assigned to the control group. Of the 232 patients undergoing hemodialysis, 62 were ruled out because serological tests for hepatitis B or C or HIV were posi-tive or not available, and 2 were ruled out because they were under 18 years of age. After exclusion of these patients, 168 remained eligible for the study group.
The main underlying etiologies of ESRD we-re diabetes mellitus (41; 24.4%), hypertension (40; 23.8%), glomerulopathy (27; 16.1%), polycystic kid-ney disease (8; 4.8%), unknown causes (35; 20.8%), and miscellaneous causes (17; 10.1%). Patients with concomitant diabetes and hypertension were assigned to diabetes group, and patients with lupus erythema-tosus were assigned to glomerulopathy group. Both groups had similar patterns of sex distribution (Chi-square =0.005; p=0.942). Table 1 shows the conti-nuous variables studied and the statistical differen-ces between the controls and hemodialysis patients.
Patients undergoing hemodialysis were older (p<0.014), had larger spleens (p<0.001), lower hemoglobin levels (p<0.001), higher leukocyte (p=0.021), neu-trophil (p<0.001), and monocyte (p<0.001) counts, and lower lymphocyte (p<0.001) and platelet counts (p=0.001) than controls (Table 1). Using a threshold value of <150,000/mm3 or >450,000/mm3 for
pla-telet count, the present study showed a 16.0% inci-dence of thrombocytopenia in hemodialysis patients and a 1.9% incidence of thrombocytopenia in the control group (Chi-square = 7.233; p=0.007), while there was 0.6% incidence of thrombocytosis in he-modialysis patients and 0.0% incidence of throm-bocytosis in the control group (Chi-square = 0.327; p=0.755).
There was a greater distribution of spleen size in the study group (minimum = 51.8 mm, maximum 149.7 mm, range = 97.9 mm) than in the controls (minimum = 63.3 mm, maximum 139.6 mm, range = 76.3 mm). The correlation coefficient between spleen size and age in the controls and patients on hemo-dialysis was quite similar (Figure 1). Among patients on hemodialysis, the comparison of the first and third tertile of spleen size revealed that patients with smal-ler spleens were predominantly women (p=0.029), older (p=0.004), had statistically significant higher platelet counts (p=0.023) (Table 2), and a lower in-cidence of thrombocytopenia (10.9% vs 25.9%; Chi-Square = 4.101; p=0.043), but the incidence of throm-bocytosis was similar in both groups (1.8% vs 0.0%; Chi-Square = 0.991; Fisher’s Exact Test = 0.505). tAble 1 ComparisonbetweenControlgroupandend-stagerenaldisease (esrd) patientsonhemodialysis
Mann-Whitney test was used unless otherwise specified. *Chi-Square test.
Variable Controls, n=75 ESRD, n=168 p
Sex, male* 45.3 % 45.8 % 0.942 Age, years 44.87±14.75 49.89±16.79 0.017 Spleen size, mm 96.55±16.03 106.41±17.07 <0.001 Hematocrit, % 41.16±4.05 29.09±7.79 <0.001 Hemoglobin, g/dL 13.64±1.47 9.39±2.54 <0.001 Leucocytes, cells/mm3 7113±2141 8184±3485 0.049 Neutrophils, cells/mm3 4184±1831 5612±3135 <0.001 Lymphocytes, cells/mm3 2217±725 1654±789 <0.001 Monocytes, cells/mm3 478±177 637±342 0.001 Platelets, cells/mm3 260415±63210 222025±75281 <0.001 Creatinine, mg/dL 0.88±0.19 7.67±3.02 <0.001
No association was found between diabetes mellitus or glomerulopathy and the smallest or largest terti-les of spleen size (smalterti-lest: 81.0% vs 19.0%; largest: 66.7% vs. 33.3%; Chi-Square = 0.952; Fisher’s Exact Test = 0.277) (Table 2).
Moreover, in this study, the use of a control group increased the reliability of the results (Table 1). It is well-known that men have larger spleens than women17. Therefore, it is worth mentioning that
the two groups in this study were sex-matched. On the other hand, the difference in mean age of bo-th groups deserves some comments. Albo-though, in this study, the subjects in the control group we-re younger than the subjects in the hemodialysis group, the effect of age on spleen size was the op-posite of what one would expect based on the re-sults. That is, subjects in the hemodialysis group (older) should have smaller spleens than subjects in the control group (younger). Moreover, Figure 1 highlights this problem, showing that the rela-tionship between age and spleen size in the con-trols and hemodialysis patients had no effect on the correlation coefficient (Figure 1). However, the imaginary straight line that describes the trajec-tory of the data of both correlations was almost parallel, and the line of the hemodialysis group was higher that that of the controls, indicating that for each age the spleen size is larger in this group. Therefore, the difference in spleen size in the controls and hemodialysis group could not be attributed to differences in sex or age distribution in both groups. If young patients on hemodialysis will develop age-related decreases in spleen size, despite continuing treatment, can only be addres-sed by means of a longitudinal study.
Figure 1. Correlation between spleen size and age in controls and
end-stage renal disease patients undergoing hemodialysis.
d
IscussIonThe most important contribution of this study is that it confirmed the finding of previously published reports about enlarged spleens in patients under-going hemodialysis. Indeed, by means of sonogra-phy we were able to reproduce the results of studies carried out using the estimated volume by scintigra-phy9 and weight at autopsy8 and after splenectomy7.
tAble 2 Comparisonbetweenfirst (smaller) andthird (larger) tertilesofspleensizeinend-stagerenaldisease
(esrd) patientsundergoinghemodialysis
Variable Smaller, n=58 Larger, n=55 p
Sex, male* 41.2 % 58.8 % 0.050 DM vs glomerulopathy* 81.0% vs 66.7% 19.0% vs. 33.3% 0.277 Age, years 55.67±15.63 43.31±15.32 <0.001 Dialysis vintage, mo 13.45±25.66 28.64±44.81 0.256 Spleen size, mm 88.77±8.95 125.43±9.76 <0.001 Hematocrit, % 28.42±6.62 29.94±9.12 0.617 Hemoglobin, g/dL 9.19±2.15 9.65±2.92 0.801 Leucocytes, cells/mm3 8319±3542 7596±3676 0.109 Neutrophils, cells/mm3 5601±3210 5123±3271 0.163 Lymphocytes, cells/mm3 1753±999 1638±703 0.559 Monocytes, cells/mm3 679±360 542±284 0.059 Platelets, cells/mm3 233891±69702 203463±78656 0.023 Creatinine, mg/dL 7.59±3.03 8.18±2.98 0.226
The effect of the underlying cause of ESRD was assessed by comparison of diabetes, a condition not mainly related to immune responses, with glomeru-lopathy, a group of conditions in which the immune system plays a key role in the pathophysiology of the disease. Moreover, in the latter case, the treatment in-cludes many drugs that suppress the immune system. Since no association has been found between glome-rulopathy or diabetes with spleen size, it is reasonable to wonder if the underlying disease or treatment befo-re the start of hemodialysis has an effect on the spleen size of these patients. That is, the effect of ESRD on hemodialysis itself might be the cause of the enlarge-ment of the spleen. In support of these thoughts, data from autopsies of patients with chronic glomerulo-nephritis showed that spleens were more than twice as heavy in patients on hemodialysis (173±15 g) than those not on hemodialysis (81±15 g)8.
In the past, splenomegaly has been attributed to venous congestion secondary to fluid overload, vi-ral hepatitis, cirrhosis, or stimulation of the immune system by chronic bacterial or viral infections, or the presence of foreign particles in the pulp9. In the
pre-sent study, viral infections were excluded. The pa-tients were in outpatient hemodialysis without need of further treatment of fluid overload. Foreign par-ticles in the spleen pulp are out of the scope of this study. Therefore, it is reasonable to speculate that the increased spleen may result from hemodialysis itself.
Based on this finding, it is appropriate to point out that despite development of new techniques to improve biocompatibility of medical polymers used in hemodialysis devices in recent decades, this study showed that the effect of hemodialysis on spleen size is the same as that reported in previous work. The lower platelet count and higher incidence of throm-bocytopenia in patients than controls suggest increa-sed splenic platelet destruction.
The dispersion of spleen size in the hemodialy-sis group was greater than that of the controls. As a consequence, the patients located in the extre-me tails of the distribution showed smaller or lar-ger spleens. These patients were included in the lo-west and highest tertiles of spleen size, respectively.
In comparison to the highest tertile, patients with a smaller spleen had statistically significant higher pla-telet counts (p=0.023) (Table 2), a finding that sug-gests that different spleen sizes have different effects on the removal of platelets. However, it was not pos-sible to determine the underlying mechanism: small spleens associated with less sequestration or large spleens associated with more sequestration. The ex-treme values (small and large) of spleen size in the tails of the distribution might be the anatomical basis for the speculation about the occurrence of hyposple-nism and hypersplehyposple-nism in patients on hemodialysis.
In patients on hemodialysis, there are two theore-tical consequences of hyposplenism we should keep in mind. First, the role of hyposplenism in arteriovenous fistula loss should not be neglected. Hyposplenism can be accompanied by thrombocytosis18-19, which might
lead to increased risk of thromboembolic events20-21.
In post-splenectomy, the hypercoagulable state due to thrombocytosis probably contributes to the increased risk of fatal myocardial ischemia22. In functional
hy-posplenism, pathological findings are quite similar to those found in splenectomized patients20,23-24. Based on
this evidence, it is reasonable to speculate whether pa-tients on hemodialysis with features of hyposplenism, are at the same risk of vascular access events or vascu-lar access failure, as reported in abnormalities of mean platelet volume25-26. Second, the main adverse events
of hyposplenic states are immunological and infec-tious events21. Hyposplenism might impair the
antibo-dy response to vaccination27-29, including hepatitis B
vaccination30. In patients on regular hemodialysis, the
overall primary vaccine-induced response to hepatitis B vaccination was impaired in a similar fashion31.
The occurrence of hypersplenism in hemodialyzed patients is well documented10,32. In cases of
hypers-plenism treated with splenectomy or partial embo-lization, the clinical features of hypersplenism were leucopenia or pancytopenia10,32. The reversion of the
isolated thrombocytopenia to a normal count af-ter splenectomy has also been reported33. Although
heparin-induced thrombocytopenia has been clai-med to be associated with hemodialysis, according to some studies, the decreased platelet count was similar to the alternative anticoagulant regimen34.
Viral hepatitis (B or C) is another factor associated with thrombocytopenia in ESRD patients undergoing hemodialysis35-36. However, in our study, every
pa-tient received only heparin as an anticoagulant regi-men, and patients with viral hepatitis (B or C) were excluded. Therefore, possible effects of heparin or vi-ral hepatitis are unsuitable for explaining the cause of thrombocytopenia in a particular tertile of spleen size. However, it is reasonable to assume that heparin-in-duced thrombocytopenia could have partially blunted the development of thrombocytosis in patients with a small spleen.
In the past, pancytopenia with excessive trans-fusion requirements10 or a large spleen along with
splenomegaly aroused suspicion of hypersplenism37.
Today, in selected patients, this diagnosis should still be kept in mind. In the current study, patients with larger spleens had lower platelet counts, a hematolo-gical feature commonly found in hypersplenism.
Even though there is large evidence of spleen en-largement in hemodialyzed patients in the literature, it is believed that this concept may have no implica-tions in clinical practice38.
The weakness of this study was the same as other cross-sectional studies, that is, no cause and effect can be determined. Moreover, although the main theore-tical implications of small and large spleens (i.e., hy-posplenism and hypersplenism) are suggested by pla-telet counts, none of these conditions has been further assessed with appropriated methods.
In conclusion, patients on hemodialysis have lar-ger spleens than controls and a large dispersion of size. Patients with smaller and larger spleens were associated with higher and lower platelet counts, res-pectively. These findings raise speculation of the oc-currence of hyposplenism and hypersplenism in this group of patients.
A
uthoR’
sc
ontRIbutIonNordeval Cavalcante Araújo contributed to the conception and design of study, data collection, analy-sis and interpretation of data, draft of the manuscript, critical revision of the manuscript for important in-tellectual content, and final manuscript approval for submission and publication.
José Hermógenes Rocco Suassunacontributed to the conception and design of study, and critical revision
c
onflIct ofI
nteRestThe authors declare that they have no conflict of interest related to the publication of this manuscript.
R
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Erratum
In the article “The spleen size in patients undergoing hemodialysis”, with DOI code number 10.1590/2175-8239-jbn-2020-0116, published at Brazilian Journal of Nephrology, 2020, on the keywords:
Where it was written: Polysomnography Should read: Sonography
